ADHD in Children and Adolescents: Current Concepts for Parents and Educators

1
ADHD in Children and Adolescents Current
Concepts for Parents and Educators

• The Family Center by the Falls
• Case Western Reserve University
• Presented at Geauga Families First Council
• Chardon, Ohio
• May 5, 2004

2
Educational Objectives

• Review current concepts as to causes of ADHD
• Describe other conditions commonly associated
  with ADHD
• Outline appropriate diagnostic strategies when
  evaluating children for ADHD
• Discuss treatment strategies for patients with
  ADHD, including the benefits and risks of
  commonly used medications
• Identify strategies for parents and teachers to
  best serve children with ADHD in academic settings

3
ADHDEtiology
ADHD is a heterogeneous behavioral disorder with
multiple possible etiologies
Genetic Origins
Neuroanatomic Neurochemical
ADHD
CNS Insults
Environmental Factors
CNS Central Nervous System
4
ADHDImaging Studies Summary

• Results support prominent role of
• frontal lobe dysfunction in ADHD
• cortical-subcortical circuits
• Neuroimaging techniques are not valid tools for
  ADHD diagnosis

5
ADHDTwin Studies
Heritability
6
ADHDSibling Studies
Occurrence of ADHD in Siblings of ADHD Children
50

• Full Siblings
• Half-Siblings
• Siblings of Controls

26
9
9
Safer (1973)
Welner et al (1977)
Safer. Behav Genet 19733175. Welner et al. J
Nerv Ment Disease 1977165110.
7
ADHDFamily Studies
ADHD in first-degree family members of children
with ADHD
Percent
8
ADHDMolecular Genetics

• Specific genes associated with ADHD
• rare mutations in the human thyroid receptor-?
  gene on chromosome 3
• dopamine transporter gene (DAT1) on chromosome 5
• dopamine receptor D4 gene (DRD4) on chromosome 11

Hauser et al. N Engl J Med 1993328997. Gill et
al. Mol Psychiatry 19972311. Swanson et al.
Mol Psychiatry 1998338.
9
ADHDOther Contributing Factors

• Maternal smoking
• Fetal exposure to drugs, alcohol
• Premature birth
• Low socioeconomic status
• Physical and/or sexual abuse?

10
ADHDEtiology Summary

• No single cause to explain the vast majority of
  ADHD cases
• Data support a biologic basis for ADHD
• Future research may more fully elucidate the
  roles of neurophysiology, genetics, and
  environment in producing this disorder

11
ADHDImpact

• ADHD is the most commonly diagnosed behavioral
  disorder of childhood
• Estimated to affect 3 to more than 10 of
  school-age children
• Many patients have persistent features and
  impairment well into adulthood

ADHD Practice Parameters. JAACAP 19973689S.
12
ADHD Worldwide Prevalence in School Age
Children
Site, Year
Criteria
Prevalence
Goldman et al. JAMA 19982791103.
13
ADHDPrevalence and Gender

• Male/female ratio in school-age children
• 31 to 91 in clinic-referred samples
• 21 in community-based samples
• Referral bias may explain these differences
• Meta-analysis of girls vs boys with ADHD show
  girls
• are less hyperactive
• have fewer conduct disorder diagnoses
• have lower rates of other externalizing behavior

Elia et al. N Engl J Med 1999340780. Arnold. J
Abnorm Child Psychol 199624555. Gaub and
Carlson. JAACAP 1997361036.
14
ADHD Persistence Into Adolescence and Adulthood
Percent Persistence
15
ADHDCourse of the Disorder
Percentage with normalized functioning at 4-year
follow-up
Biederman et al. J Pediatr 1998133544-551.
16
ADHDPotential Areas of Impairment

• School/academics
• Interpersonal relationships
• Trouble with the law
• Smoking and substance abuse
• Injuries
• Motor vehicle accidents
• Occupational/vocational

ADHD Practice Parameters. JAACAP 19973689S.
17
ADHDImpact at School

• ADHD covered under
• Individuals with Disabilities Education Act
  (IDEA)
• Section 504 of the Rehabilitation Act
• schools are mandated to provide special
  educational services or accommodations

18
ADHDImpact at School

• Difficulties in learning
• Poor organization and study skills
• Difficulty sitting still and taking tests
• Failure to complete or turn in homework
• Lower than expected or erratic grades and
  achievement test scores
• Disruptive behavior
• Poor peer relationships
• Special class placement
• Grade retention
• Suspension
• Expulsion
• Failure to graduate

ADHD Practice Parameters. JAACAP
19973689S. Greenhill. J Clin Psychiatry
19985933.
19
ADHDImpact on Socialization

• Children with ADHD often rejected by peers
  because of
• Impulsive aggression
• Impulsivity/hyperactivity
• excessive talking (motor mouth)
• poor listening skills
• Failure to comply with rules
• poor participants in team sports
• Adolescents with ADHD have been rated as
• Less socially competent
• Involved in fewer social activities
• Having fewer friends

ADHD Practice Parameters. JAACAP
19973689S. Greenhill. J Clin Psychiatry
19985933. Barkley et al. JAACAP 199130752.
20
ADHDImpact on Family

• Parents of children with ADHD experience higher
  levels of

• Stress
• Self-blame
• Social isolation
• Depression
• Marital discord

Mash and Johnston. J Clin Child Psychol
199019313. Murphy and Barkley. Am J
Orthopsychiatry 19966693.
21
ADHDDelinquency

• In 84 clinically-referred adolescents with ADHD
• However, a diagnosis of conduct disorder is more
  predictive of later delinquent or criminal
  behavior than is ADHD

Each measure vs controls Plt0.001
Barkley et al. JAACAP 199130759. Foley et al.
Bull Am Acad Psychiatry Law 199624333.
22
ADHDCigarette Smoking

• Adult patients with ADHD smoke more and have more
  difficulty in quitting
• Children with ADHD smoke more and start at an
  earlier age than controls

Pomerleau et al. J Subst Abuse 19957373. Milberg
er et al. JAACAP 19973638.
23
ADHD and Psychoactive Substance Use Disorders
(PSUD) in Youth

• 4-year follow-up of clinically referred sample
  of boys 6 to 17 years old at baseline

With PSUD at Follow-up
15
15
Biederman et al. JAACAP 19973621.
24
ADHD PSUD in Adults

• Adults of both genders with ADHD vs non-ADHD,
  healthy adults

Lifetime Rate of PSUD in Referred ADHD Adults
27
55
Biederman et al. Biol Psychiatry 199844269.
25
ADHD Risk of Substance Abuse
Sharp rise in PSUD between mid-adolescence and
adulthood
15
15
27
55
Biederman et al. JAACAP 19973621. Biederman et
al. Biol Psychiatry 199844269.
26
ADHDPharmacotherapy and Substance Abuse
Overall Rate of PSUD
Plt0.001
33
Percent of Group
13
10
Unmedicated ADHD (N45)
Medicated ADHD (N117)
Control (N344)
Biederman et al. Pediatrics 1999 In press.
27
ADHD and Psychoactive Substance Use Disorders
(PSUD)

• 4-year follow-up of a clinically referred sample
  of boys 6 to 17 years old at baseline (ADHD
  N140 control N120)
• no difference in the rate of alcohol or drug
  abuse between groups (15 vs 15)
• Risk for PSUD mediated by conduct disorder and
  bipolar disorder (with or without ADHD)
• Adults with ADHD (N239) vs controls (N268)
• significantly greater lifetime rate of PSUD than
  controls (55 vs 27)
• Age of onset of PSUD in subjects with ADHD
  averaged 3 years earlier than controls (late
  adolescence/early adulthood)
• ADHD was a significant risk factor independent of
  comorbid diagnoses

Biederman et al. JAACAP 19973621. Biederman et
al. Biol Psychiatry 199844269.
28
ADHDInjuries

• Data from 70 hospitals in the US National
  Pediatric Trauma Registry regarding
  hospital-admitted injury

• Controls ADHD
• Injured as pedestrian 28 18
• Injured as bicyclist 17 14
• Self-inflicted injury 1.3 0.1
• Injured multiple body regions 57 43
• Head injuries 53 41

DiScala et al. Pediatrics 19981021415.
29
ADHDMotor Vehicle Driving

• Study of 16 to 22 year olds
• 35 with ADHD (not on medication)
• 36 controls

• Significantly more drivers with ADHD
• drove without a license
• had licenses revoked or suspended
• had multiple crashes (2)
• had multiple traffic citations (3), especially
  for speeding

• Subgroups of ADHD with comorbid oppositional
  defiant or conduct disorder were at highest risk

Barkley et al. Pediatrics 199392212.
30
ADHDOccupational Status

• Despite similar educational levels and IQ scores,
  individuals with ADHD (not taking medication)
  display
• significantly more academic problems in school
  (25 repeat a grade)
• trends toward lower occupational attainment

Seidman et al. Biol Psychiatry 199844260. Bieder
man et al. Am J Psychiatry 19931501792.
31
ADHD Etiology and Impact Summary

• ADHD is a neurobehavioral disorder with a
• complex etiology
• neurobiologic basis
• strong genetic component
• ADHD
• affects millions of people of both genders
• persists through adolescence and adulthood in a
  high percentage of cases
• can have negative impact on multiple areas of
  functioning

32
ADHD Diagnosis

• ADHD is a behavioral syndrome that can be
  diagnosed and treated
• not merely a result of unreasonable expectations
  and a fast-paced society
• Diagnosis is made on historical and subjective
  evidence

33
ADHDDomains of Impairment

• Peer relationships
• Family relationships
• Adult relationships
• School or occupational functioning
• Leisure activities

Domains of Impairment
34
ADHD DSM-IV Criteria
Inattention
Six or more of the following ? manifested often

• Inattention to details/ makes careless mistakes
• Difficulty sustaining attention
• Seems not to listen
• Fails to finish tasks

• Difficulty organizing
• Avoids tasks requiring sustained attention
• Loses things
• Easily distracted
• Forgetful

American Psychiatric Association. DSM-IV, 1994.
35
ADHD DSM-IV Criteria
Impulsivity/Hyperactivity
Six or more of the following ? manifested often

• Impulsivity
• Blurts out answer before question is finished
• Difficulty awaiting turn
• Interrupts or intrudes on others

• Hyperactivity
• Fidgets
• Unable to stay seated
• Inappropriate running/climbing (restlessness)
• Difficulty in engaging in leisure activities
  quietly
• On the go
• Talks excessively

American Psychiatric Association. DSM-IV, 1994.
36
ADHDDSM-IV Criteria

• Symptoms of inattention
• OR impulsivity/hyperactivity
• (Hyperactivity is NOT required for a diagnosis)
• have persisted for ? 6 months
• are more frequent and severe than is typical of
  the individuals level of development
• have onset prior to age 7
• cause some impairment in two or more settings
• cause significant impairment in social, academic,
  or occupational functioning
• are not better accounted for by another mental
  disorder

American Psychiatric Association. DSM-IV, 1994.
37
ADHDDSM-IV Subtypes

• ADHD Predominantly Inattentive Type
• criteria met for inattention but not
  for impulsivity/hyperactivity
• ADHD Predominantly Hyperactive-Impulsive Type
• criteria met for impulsivity/hyperactivity but
  not for inattention
• ADHD Combined Type
• criteria are met for both inattention and
  impulsivity/hyperactivity

Inattention
Impulsivity/Hyperactivity
Inattention
Impulsivity/Hyperactivity
American Psychiatric Association. DSM-IV, 1994.
38
ADHDInattentive Subtype

• More often seen in pediatric and primary care
  practice
• Commonly associated with academic dysfunction
• More often identified in girls with ADHD
• Compared to other subtypes

• More likely to be characterized as
• sluggish/drowsy
• spacey/daydreamer
• socially withdrawn
• having depressed mood
• and anxiety

• Less likely to have
• serious conduct
• problems
• aggression
• impulsivity

Greenhill. J Clin Psychiatry 199859(suppl
7)31. ADHD Practice Parameters. JAACAP
19973685S.
39
ADHDClinical Presentation
Preschool (Ages 35)

• Motor restlessness (always on the go)
• Aggressive (hits others)
• Spills things
• Insatiable curiosity
• Dangerously daring
• Vigorous and often destructive play (breakage of
  toys and household objects accidental injuries
  common)
• Demanding, argumentative
• Noisy, interrupts
• Excessive temper tantrums (more severe and
  frequent)
• Low levels of compliance

Greenhill. J Clin Psychiatry 199859(suppl
7)31. Conners and Jett. ADHD in Adults and
Children. Compact Clinicals 1999.
40
ADHDClinical Presentation

• Easily distracted
• Homework poorly organized, contains careless
  errors, often not completed
• Blurts out answers before question completed
  (often disruptive in class)
• Often interrupts or intrudes on others and
  displays aggression (difficulties in peer
  relationships)
• Fails to wait turn in games
• Often out of seat
• Perception of immaturity (unwilling or unable
  to complete chores at home)

Greenhill. J Clin Psychiatry 199859(suppl
7)31. Conners and Jett. ADHD in Adults and
Children. Compact Clinicals 1999.
41
ADHDClinical Presentation

• May have a sense of inner restlessness (rather
  than hyperactivity)
• School work disorganized and shows poor
  follow-through fails to work independently
• Engaging in risky behaviors (speeding and
  driving mishaps)
• Poor self-esteem
• Poor peer relationships
• Difficulty with authority figures

Greenhill. J Clin Psychiatry 199859(suppl
7)31. Conners and Jett. ADHD in Adults and
Children. Compact Clinicals 1999.
42
ADHDClinical Presentation
Adulthood

• Disorganized, fails to plan ahead
• Forgetful, loses things
• Difficulty in initiating and finishing projects
  or tasks
• Misjudges available time
• Inattention/concentration problems
• May have job instability and marital difficulties
• Poor anger control

Greenhill. J Clin Psychiatry 199859(suppl
7)31. Conners and Jett. ADHD in Adults and
Children. Compact Clinicals 1999.
43
ADHDDifficulties in Diagnostic Process

• Often is a highly subjective measure, means
  different things at different ages
• Age of onset criteria (before age 7) has been
  questioned
• No specific diagnostic test available
• Lack of specificity in symptoms
• Symptoms may not be evident in office interviews
  (history very important)
• Low rate of concordance between different
  informants (parents, teachers, patient)

Applegate et al. JAACAP 1997361211. Barkley and
Biederman. JAACAP 1997361204. Greenhill. J Clin
Psychiatry 199859(S7)31. ADHD Practice
Parameters. JAACAP 19973685S.
44
ADHDImportance of Diagnosis

• Eligibility for special educational services
• Determination of course of treatment
• Plan for treatment monitoring
• Linking treatment to prognosis

Conners and Jett. ADHD in Adults and Children.
Compact Clinicals 1999.
45
ADHD Common Comorbid Diagnoses
Prevalence in Children with ADHD
Conduct Disorder and/or Oppositional Defiant
Disorder
50
Learning Disorders
At least 20 - 30
Depressive Disorders
ADHD
9 - 38
25
Anxiety Disorders
Pliszka. J Clin Psychiatry 199859(suppl
7)50. Hudziak et al. JAACAP 199837848.
46
ADHDDifferential Diagnosis

• Differential Conditions
• Age-appropriate high activity
• Mental retardation
• Thyroid disorders
• Absence seizures
• Sensory deficits
• Tourettes syndrome or chronic tic disorder
• Sleep disorders
• Aspergers or autism
• Psychosis
• Substance abuse

• Coexisting Conditions
• Conduct disorder
• Oppositional defiant disorder
• Learning disabilities
• Anxiety disorder
• Mood disorder
• Speech/language disorder

Zametkin and Ernst. N Engl J Med
199934040. Baumgaertel and Wolraich. Amb Child
Health 1998445. ADHD Practice Parameters.
JAACAP 19973685S.
47
ADHDDifferential Diagnosis

• Environmental Conditions
• Abuse or neglect
• Family adversity
• Situational stress
• High intelligence with
• inappropriate school
• placement

• Possible Etiologic Conditions
• Chronic lead poisoning
• Post-traumatic or infectious
• encephalopathy
• Fetal alcohol syndrome
• Fragile X syndrome
• Phenylketonuria

Zametkin and Ernst. N Engl J Med
199934040. Baumgaertel and Wolraich. Amb Child
Health 1998445. ADHD Practice Parameters.
JAACAP 19973685S.
48
ADHDDiagnostic Assessment Techniques
Interview and History
Standardized Assessment Measures
Observation
Physical and Neurologic Exam
Conners and Jett. ADHD in Adults and Children.
Compact Clinicals 1999.
49
ADHDInterview and History

• Assessment of
• Medical history
• Developmental history
• Family and individual psychiatric history
• Academic or occupational performance
• Social relationships
• Family and home environment
• Individual functioning (eg, mood, self-esteem)

Conners and Jett. ADHD in Adults and Children.
Compact Clinicals 1999. Baumgaertel and
Wolraich. Amb Child Health 1998445. Greenhill.
J Clin Psychiatry 199859(suppl 7)31.
50
ADHDRating Scales

• Useful, easy to administer assessment tools
• Available for parent, teacher, self-report
• Quantifies how behavior deviates from norms
• Not to be used alone to make or refute diagnosis
• Helpful in assessing and monitoring response to
  treatment

Goldman. JAMA 19982791100. Conners and Jett.
ADHD in Adults and Children. Compact Clinicals
1999.
51
ADHDRating Scales

• Preschool
• The Early Childhood Attention Deficit Disorder
  Evaluation Scale (ECADDES)
• Elementary School
• Child Behavioral Checklist (CBCL) - Parent,
  Teacher, or Youth forms
• Conners Parent and Teacher Rating Scales (CPRS
  and CTRS)
• Adolescent
• Conners/Wells Adolescent Self Report of Symptoms
  (CAAS)
• Adolescent Symptom Inventory-4 (ASI-4)
• Adults
• Conners Adult Attention-Deficit Rating Scale
  (CAARS)

Quinn. ADD Diagnosis and Treatment.
Brunner/Mazel 1997 Conners and Jett. ADHD in
Adults and Children. Compact Clinicals 1999.
52
ADHDDiagnostic Assessment

• Prior to office visit try to obtain
• Clarification of reason for visit (chief
  complaint)
• School records (placement, achievement, IQ tests)
• Behavior reports (teacher and parent rating
  scales)
• Reports of previous medical and psychologic
  evaluations

Baumgaertel and Wolraich. Amb Child Health
1998445. Greenhill. J Clin Psychiatry
199859(suppl 7)31.
53
ADHDDiagnostic Assessment

• Office visit(s)
• Parent and patient interview
• symptoms of ADHD and severity of impairment
• consider developmental level and age
• possible comorbidity
• family history
• psychosocial stressors
• Observe childs behavior and parent-child
  interaction (often of limited value)
• Evaluate medical and neurological status

Baumgaertel and Wolraich. Amb Child Health
1998445. Greenhill. J Clin Psychiatry
199859(suppl 7)31.
54
ADHDDiagnostic Assessment

• Consider the parent in the diagnostic assessment
• ADHD is highly heritable, and parents with ADHD
  may have problems with
• time management, organization, memory, impulse
  control, overall consistency, and other
  psychopathology
• potential for serious negative impact on any
  treatment program that is implemented

Murphy and Barkley. Am J Orthopsychiatry
19966693.
55
ADHDDiagnostic Assessment

• Identify the areas of impairment
• What are the problems in daily life functioning?
• Ultimate targets in treatment are not the
  symptoms of ADHD, rather the impairments caused
  by these symptoms

56
ADHDDiagnostic Assessment

• Response to stimulant medication does not
  validate a diagnosis of ADHD
• children and adults without the disorder have
  cognitive and behavioral responses similar to
  those of patients with ADHD

Elia et al. N Engl J Med 1999340783.
57
ADHDWhen to Refer
Primary care providers may consider referring when

• Suspect mental disorders other than ADHD as
  primary concern, or ADHD with significant
  comorbidity
• child psychiatrist
• pediatric neurologist
• developmental pediatrician
• Suspect other neurologic disorder (eg, seizure
  disorder)
• pediatric neurologist
• Complicated cases if clinician is uncomfortable
  about diagnosis or treatment

Baumgaertel and Wolraich. Amb Child Health
1998445.
58
Diagnosis of ADHDSummary

• Diagnosis relies strongly on DSM-IV criteria in
  domains of
• inattention
• impulsivity
• hyperactivity
• Comorbidity is common
• Diagnostic assessment includes a thorough
  gathering of information from multiple sources
• Treatment should be targeted to and assessed by
  changes in specific areas of impairment

59
ADHDComponents of Treatment
Education
Psychosocial Interventions
Medical Interventions
60
ADHDTreatment Planning

• Goals
• reduce major symptoms of ADHD
• improve functioning in areas of impairment
• Plan
• address individual target symptoms
• use rating scales and/or daily report cards at
  baseline and to monitor progress
• reassess and modify as necessary

Conners and Jett. ADHD in Adults and Children.
Compact Clinicals 1999. ADHD Practice
Parameters. JAACAP 19973685S.
61
ADHDTreatment Planning

• Considerations
• patients age and developmental level
• school environment
• home environment
• target symptoms and behaviors
• areas with greatest degree of impairment should
  be treated first
• Treatment decisions should be guided by what is
  realistic and in the best interest of the patient
  

ADHD Practice Parameters. JAACAP
19973685S. Baumgartel and Wolraich. Ambul Child
Health 1998445.
62
ADHDTreatment Planning

• Symptoms likely to respond to medication

• Inattention
• Impulsivity
• Hyperactivity
• Noncompliance
• Oppositional behavior
• Impulsive aggression
• Social interactions
• Academic productivity and accuracy

ADHD Practice Parameters. JAACAP
19973685S. Zametkin and Ernst. N Eng J Med
199934040.
63
ADHDTreatment Planning

• Behavioral symptoms may be addressed with
  behavior/educational modification techniques
• Skills deficits in domains of academics (ie,
  learning disabilities) require specific
  remediation and are not likely to respond
  significantly to medication or behavioral therapy

ADHD Practice Parameters. JAACAP
19973685S. Zametkin and Ernst. N Eng J Med
199934040.
64
ADHDTreatment Planning

• After consultation with the parent, and with
  parental permission, clinician should contact the
  school to
• recommend further evaluation if evidence of a
  learning disability is present
• discuss treatment and the role that the school
  plays in treatment

IDEA. Public Law 94-142. 1990. Rehabilitation Act
of 1973, Section 504.
65
ADHDPsychosocial Interventions

• ADHD not caused by poor parenting skills or a
  stressful family environment
• Environmental factors can exacerbate the symptoms
  
• Parenting techniques appropriately in tune with
  the ADHD child can improve symptoms and increase
  the childs self-esteem

ADHD Practice Parameters. JAACAP 19973685S.
66
ADHDPsychosocial Interventions

• House rules
• Appropriate commands (specific, clear, positive)
• Ignore mild inappropriate behaviors and praise
  positive behavior
• Contingency management with positive
  reinforcement (eg, a point chart) and prudent
  negative consequences (eg, privilege loss)
• Behavioral contracting in adolescent children

ADHD Practice Parameters. JAACAP
19973685S. Zametkin and Ernst. N Eng J Med
199934040.
67
ADHDPsychosocial Interventions
School Interventions

• Largely employ techniques taught in parent
  training
• Daily behavioral report cards
• serve to define target behaviors
• facilitate school-home communication and allow
  parents to provide rewards for good school
  behavior and performance
• Special classroom accommodations
• clearly and consistently posting daily schedules
• breaking assignments into smaller chunks
• providing rewards for task completion and
  consequences for rule violations

ADHD Practice Parameters. JAACAP 19973685S.
68
ADHDPsychosocial Interventions
Social Skills Training

• Sometimes used to teach the child skills needed
  in peer relationships and other settings
• ? Interaction skills ? Conflict resolution
• ? Problem-solving skills ? Anger management
• Results of studies of this strategy are
  inconsistent
• More effective when taught in group settings such
  as summer camps, school-based, and after-school
  settings

ADHD Practice Parameters. JAACAP
19973685S. Zametkin and Ernst. N Eng J Med
199934040.
69
ADHDLargely Ineffectual Interventions

• Individual psychotherapy
• Cognitive therapy
• Play therapy
• Elimination diets
• Allergy treatments
• Chiropractic therapy
• Megavitamin/mineral therapy

Elia et al. N Engl J Med 1999340780. Pelham et
al. J Clin Child Psychol 199827190.
70
ADHDMTA Study

• NIMH and US Dept of Education Multimodal
  Treatment Study of Children with ADHD (MTA)
• 14-month, multicenter, randomized, controlled
  trial
• 579 children, age 7 to 9 years, ADHD combined type

Arnold et al. Arch Gen Psychiatry 199754865.
71
ADHDMTA Treatment Arms

• Medication management only
• MPH TID, adjusted for best dose, other drugs if
  necessary algorithmic dose adjustments general
  advice and readings case management by
  pharmacotherapist
• Intensive behavioral treatment only
• parent training structured teacher consultation
  8-week, full-time, summer treatment program 12
  weeks of half-time, classroom, behavioral
  specialist case management by therapist/consultan
  t
• Medication management behavioral treatment
• Community-based care
• after assessment by investigators, parents could
  seek community care (roughly two thirds received
  medication)

MPH methylphenidate. MTA Cooperative Study
Group. Arch Gen Psychiatry 1999561073.
72
ADHDMTA Results
All treatments led to improvement in core ADHD
symptoms
Medication management behavioral treatment
Medication management alone
Nearly equal effectiveness and superior to both
Behavioral treatment alone
Community based treatment
MTA Cooperative Study Group. Arch Gen Psychiatry
1999561073.
73
ADHDMTA Results

• Medication behavioral treatment
• superior to other three conditions in improving
  reading achievement scores
• Behavioral treatment alone
• superior to community-based medication treatment
  in improving ADHD-related and internalizing
  symptoms in children with ADHD and comorbid
  anxiety disorder

MTA Cooperative Study Group. Arch Gen Psychiatry
1999561088.
74
ADHDMedical Interventions

• General Principles
• Weigh risks of treating vs not treating
• Outline expected benefits
• Institute concurrently or after behavioral and
  psychoeducational techniques have been employed
• in some cases severe impulsivity, noncompliance,
  or aggression are present making need for
  medication urgent

ADHD Practice Parameters. JAACAP
19973685S. Zametkin and Ernst. N Eng J Med
199934040.
75
ADHDStimulants

• Of pharmacologic options available for ADHD,
  stimulant medications are the
• Most studied
• Most commonly used
• Most effective
• First-line agents for treatment

ADHD Practice Parameters. JAACAP
19973685S. Spencer et al. JAACAP 199635409.
76
ADHDStimulants

• Stimulant drugs effective in all age groups
• Vast majority of controlled studies in school-age
  children (6- to 12-years old)

Studies of Stimulants for ADHD by Age Group
Preschool
Spencer et al. JAACAP 199635409. Elia et al. N
Eng J Med 1999340780.
77
In ADHDStimulants Found to Improve
AND
Core Symptoms

• Inattention
• Impulsivity
• Hyperactivity

• Noncompliance
• Impulsive aggression
• Social interactions
• Academic productivity and accuracy

ADHD Practice Parameters. JAACAP
19973685S. Zametkin and Ernst. N Eng J Med
199934040.
78
ADHDStimulants

• Methylphenidate (Ritalin, Concerta)
• Dextroamphetamine (Dexedrine, DextroStat)
• Amphetamine mixed salts (Adderall)
• contains equal parts d-amphetamine sulfate,
  d,l-amphetamine sulfate, d,l-amphetamine
  aspartate, and d-amphetamine saccharate
• Pemoline (Cylert)
• generally not considered a first-line agent
  because of liver toxicity

79
ADHDStimulant Dosing

• Medication should be given 7 days/week during
  initiation of therapy and through titration to
  optimal effect
• This strategy allows
• parents of children receiving medication to see
  medication effects and benefits in off-school
  hours
• better assessment of efficacy and side effects

Zametkin and Ernst. N Eng J Med 199934040.
80
ADHDStimulant Dosing

• After titration phase
• continue on 7 days/week?
• consider impairment outside of school
• give only for school 5 days/week?
• some patients may have less serious impairment
  outside of school (or work) and do not require
  medication for these times
• Careful consideration must be given to all areas
  where impairment may be occurring

Zametkin and Ernst. N Eng J Med 199934040.
81
ADHDAcidifying Agents and Stimulants

• Acidifying agents ionize methylphenidate and
  amphetamine, decreasing absorption from the GI
  tract
• Foods to avoid
• soft drinks, lemonade, Koolade?, Gatorade?, high
  vitamin cereals, granola bars, power bars
• Medications to avoid
• oral suspensions/antibiotics, vitamin C

Physicians Desk Reference. 1999.
82
ADHDLonger-Acting Stimulants

• Advantageous in
• patients experiencing very brief duration of
  effect from standard formulations
• situations where frequent dosing is inconvenient,
  stigmatizing, or impossible (in-school dosing)
• Ritalin SR and Dexedrine Spansules
• less reliable effect than short-acting
• overall duration of response often not
  significantly longer because of delayed onset of
  action
• Adderall, Dexedrine, DextroStat offer
  advantages over standard Ritalin in duration of
  effect
• Cylert need for liver function monitoring may
  outweigh advantages of longer duration of action

ADHD Practice Parameters. JAACAP
19973685S. Findling and Dogin. J Clin
Psychiatry 199859(suppl 7)42.
83
ADHDResponse to Stimulants
Meta-analysis of within-subject comparative
trials evaluating response to stimulant
medications
38
36
Best Response (Percent)
26
DEX
MPH
Equal response to either stimulant
DEXDextroamphetamine (Dexedrine, others)
MPHmethylphenidate (Ritalin, others)
Greenhill et al. JAACAP 1996351304.
84
ADHDResponse to Stimulants
Meta-Analysis of Within-Subject Comparative
Trials Evaluating Response to Stimulant
Medications
41
Best Response (Percent)
28
16
AMP
MPH
Equal response to either stimulant
AMPAmphetamine (Adderall , Dexedrine,
DextroStat) MPHmethylphenidate (Ritalin,
others).
Arnold et al. J Attention Dis 20003200.
85
Implications of Greenhill, Arnold Studies

• Children with uncomplicated ADHD should receive a
  trial of an alternate stimulant if they fail an
  initial stimulant trial
• Children who are sub-optimal responders to a
  given stimulant may benefit significantly from a
  trial with an alternative stimulant-Dont rock
  the boat approach of physicians is often an
  obstacle

86
Comparison Studies Between Methylphenidate and
Amphetamine (Arnold, 2000)

• Response rate to MPH 57-68
• Response rate to AMP 69-77
• Response to either MPH or AMP in patients
  receiving both 87-92

87
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88
Relative advantages of methylphenidate (MPH) over
amphetamine (AMP) for treatment of ADHD (Arnold,
2000)

• Better with comorbid Tourettes (significant)
• Better response on CPT (significant)
• Possibly better in patients with comorbid
  learning disabilities, visuo-motor disorder
• Less anorexia, weight loss, sleep delay
  (possible)

89
Relative advantages of amphetamine (AMP) over
methylphenidate (MPH) for treatment of ADHD
(Arnold, 2000)

• More consistent day to day response
  (statistically significant)
• More patients with good/excellent response
  (probable)
• Better with comorbid CD/ODD (probable)
• May be better with high IQ (retrospective)
• Variety of SR spansule strengths, more
  consistently efficacious than SR MPH
• Longer half-life, clinical effect
• Less depression, apathy, fewer stomach aches

90
ADHDAdderall vs Ritalin
3-week, randomized, placebo-controlled trial
IOWA CTRS Inattention/Overactivity Mean Scores
Plt0.05
Plt0.05
CGI-Improvement Mean Scores (1very much
improved 7very much worse)
Adderall (N20) final mean daily dose 12.4
mg Ritalin (N20) final mean daily dose 25.2
mg Placebo (N18)
QD dosing effective in

• 70 of Adderall group
• 15 of Ritalin group

Pliszka et al. JAACAP 200039619.
91
ADHDAdderall vs Ritalin
Effect on Disruptive Behavior
Effect Size
AMS Adderall MPHmethylphenidate (Ritalin,
others)
Time

• Adderall preferred 3 to 1 over Ritalin by
  clinical staff at end of trial

Pelham et al. Pediatrics Electronic Pages
1999103e43.
92
Adderall vs. Methylphenidate in Children With
ADHD (Grcevich APA, AACAP-1999)

• Largest comparison study to date (N164)
• Adderall patients were dosed less frequently,
  less likely to require in-school dosing

93
Adderall vs. Methylphenidate in Children With
ADHD (Grcevich APA, AACAP-1999)

• Adderall and MPH equally effective by CGI
  ratings and change in GAF during treatment,
  AdderallgtMPH on CTRS, CPRS
• No statistically significant differences in side
  effects

94
ADHD(Grcevich, APA, AACAP-1999) Adderall vs
Ritalin
Time to Switching to Alternative Medication if
Started on
Probability of Staying on Initial Rx
Initial Rx
Adderall (N54) MPH (N75)
Log-Rank Test P0.0003
Time on the Drug (Days)
Grcevich et al. Presented at the Annual Meeting
of Am Psychiatric Assoc 1999.
95
ADHDAdderall vs Ritalin

• Recent comparisons of Adderall to Ritalin show
  Adderall
• At least equally effective in all studies,
  evidence of superiority in 4/6 studies (Pliszka,
  Pelham I, Pelham II, Grcevich)
• Longer acting
• Eliminates in-school dosing in many patients
• Lower likelihood of discontinuation
• Similar in side-effect profile
• Differential time-course effects of Adderall as
  compared with Ritalin may allow the tailoring of
  dosing regimens to meet the specific needs of
  patients with ADHD

Swanson et al. JAACAP 199837519. Pelham et al.
Pediatrics Electronic Pages 1999103e43.
Pliszka. Presented at 1999 Annual Meeting of Am
Psychiatric Assoc.. Grcevich. Presented at 1999
Annual Meeting of Am. Psychiatric Assoc..
96
Comparison Studies of Adderall vs.
Methylphenidate in Children, Adolescents
97
ADHDFuture Medication Options

• Concerta
• Methylphenidate Extended-Release Tablets
• Longer duration of action than other extended
  release compounds
• Comparable to tid methylphenidate in clinical
  effects, side effect profile
• Available in 18 mg, 36 mg strengths (issues
  around dosing flexibility)
• No comparison studies to Adderall, Dexedrine, SR
  Ritalin
• Cost as a factor in availability on formularies?

Pelham et al. Presented at AACAP Annual Meeting,
1999. Biederman et al. Presented at American
Academy of Neurology, 2000
98
(No Transcript)
99
ADHDFuture Medication Options

• Extended release Adderall (SLI-381) preparation
  in development-will combine equal parts of
  standard mix of amphetamine salts with salts
  encased within gel matrix (dissolves within 4-6
  hours) to mimic effect of bid dosing
• Phase III studies completed
• Preliminary results promising
• FDA approval anticipated during 2001

100
SLI381 Results Mean PERMP Number Correct by
Treatment and Session (McCracken, AACAP 2000)
X
X
X
X
X
X
X
X
0.5
1.5
4.5
6.0
7.5
9.0
10.5
12.0
Median Time (hr) Post Dose
101
SLI-381 Results Summary

• All medication regimens were effective, and
  demonstrated superiority to placebo
• 20 mg and 30 mg SLI-381 had activity comparable
  to Adderall at 1.5 hours, but maintained peak
  activity throughout the course of the school day
• Dose-dependent improvements were evident
• No adverse effect showed a clear dose-related
  pattern

102
ADHD Other Products Being Studied

• MethyPatch (Noven)-inactive compound absorbed
  through skin, metabolized into active stimulant
  in liver (phase III)
• Ritalin QD (Novartis) Spencer et al., APA,
  2000-results disappointing (phase III)
• Tomoxetine (Lilly)-selective noradrenergic
  enhancer, nearly as effective as MPH in two
  controlled studies, well-tolerated-Phase II-III
• Provigil (Cephalon)-used currently for narcolepsy
  (phase I/II)-major placebo-controlled adult trial
  recently demonstrated lack of effectiveness in
  adult ADHD, unlikely to be FDA approved

103
ADHDStimulant Dosing

• High variability in effective doses within and
  among individuals
• Decision of how many doses/day and how many
  days/week based on the severity and time course
  of target symptoms
• Medication should be given seven days/week during
  initiation of therapy and through titration to
  maximal effect this allows parents to observe
  the effect of medication throughout the day and
  provide meaningful feedback as to impact upon
  functional impairment

ADHD Practice Parameters. JAACAP 19973685S.
104
ADHDStimulant Overuse?
Epidemiologic study exploring prevalence of ADHD
and service use frequencies

• By Diagnostic Group, Numbers () of Children
  Receiving Types of Services in Previous 12 Months

ADHD (n66)
Other Diagnosis (n320)
No Diagnosis (n899)
Total (N1,285)
8 (12.1) 1 (1.5) 16 (24.2) 21 (31.8)
4 (1.3) 9 (2.8) 55 (17.2) 63 (19.7)
4 (0.4) 3 (0.3) 32 (3.6) 43 (4.8)
16 (1.4) 13 (1.1) 103 (8.0) 127 (9.9)
Stimulants Other medications School-based
services Psychosocial treatments
Jensen et al. JAACAP 199938797.
105
ADHDBupropion (Wellbutrin)

• Advantages
• may decrease hyperactivity and aggression
• may improve cognitive performance
• Double-blind, placebo- controlled studies
  demonstrate effectiveness

• Disadvantages
• Not as effective as stimulants for cognitive
  symptoms
• Available dosage forms inappropriate for younger
  children
• may decrease seizure threshold
• may exacerbate tics

ADHD Practice Parameters. JAACAP
19973685S. Biederman. J Clin Psychiatry
199859(suppl 7)4.
106
ADHDTricyclic Antidepressants

• Advantages
• may have better response in cases of comorbid
  anxiety or depression
• may be useful in patients with tic disorders
• longer duration of action

• Disadvantages
• efficacy lt stimulants
• serious potential cardiac effects in children
• need for cardiac monitoring

ADHD Practice Parameters. JAACAP
19973685S. Biederman. J Clin Psychiatry
199859(suppl 7)4.
107
Venlafaxine in Treatment of ADHD

• One small, open study (N16)
• Modest impact on behavioral sx., little impact on
  cognitive sx.
• May aggravate hyperactivity
• 25 didnt tolerate side effects
• One adult study (Findling, J. Clin. Psychiatry,
  1998) demonstrated promising results
• Both studies utilized short-acting preparation
• Olivera, J. Child Adol. Psychopharm., 1996 (4)

108
ADHDClonidine (Catapres)

• Disadvantages
• clinical effects may take several weeks
• does not affect inattention symptoms
• sedation
• risk of adverse CV effects, depression, and
  decreased glucose tolerance

• Advantages
• may be useful to treat very hyperactive or
  aggressive patient
• improves ability to fall asleep

Guanfacine (Tenex) has a more favorable
side-effect profile than clonidine but has only
been studied in open trials.
ADHD Practice Parameters. JAACAP 19973685S.
109
Guanfacine (Tenex) for ADHD

• Efficacy reported in two open studies
• Recent study by Horrigan (AACAP, 2000) described
  moderate effectiveness for ADHD symptoms
• Reported to have less sedation than clonidine,
  with better effect on cognitive sx., less effect
  for hyperactivity
• 10X less potent than clonidine
• More research (placebo-controlled studies) needed
• Hunt et al., JAACAP, 1995
• Horrigan, Presented at AACAP Annual Meeting, 2000

110
Combination Pharmacotherapy for ADHD

• Little controlled data available
• Frequently prescribed for patients with ADHD
  exacerbated by comorbid conditions
• May be beneficial for partial responders to
  stimulants who continue to experience impulsive
  or aggressive behaviors
• Helpful for physical symptoms associated with
  ADHD treatment (prolonged sleep latency) or other
  associated conditions (enuresis, tics)

111
ADHDCombination Therapy

• Stimulant antidepressant
• When to consider
• in patients with comorbid affective disorders
• TCAs in patients with enuresis refractory to
  behavioral treatment
• Precautions
• reports of sudden unexplained death in pediatric
  patients with desipramine and imipramine
• careful evaluation of medical and family history
  for cardiac symptoms and risk factors
• ECG monitoring baseline and while on chronic
  therapy

DuPaul et al. In Barkley. ADHD A Handbook for
Diagnosis and Treatment 1998510. Spencer et al.
In Barkley. ADHD A Handbook for Diagnosis and
Treatment 1998552.
112
ADHDCombination Therapy

• Stimulant clonidine
• When to consider
• in patients with extreme hyperactivity and/or
  aggression
• if sleep disturbances are associated with ADHD or
  stimulant treatment
• Precautions
• clonidine associated with slowed sinus rate and
  AV conduction
• caution with the combination may be advised in
  light of 4 sudden unexplained deaths, although
  all cases were confounded by other possible
  etiologic factors

Wilens and Spencer. JAACAP 199938614. Swanson
et al. JAACAP 199938617.
113
Texas Medication Algorithm Project

• Expert consensus conference held to determine
  algorithms for ADHD treatment in the public
  sector
• Goals improve uniformity of treatment, improve
  outcomes
• Importance of psychosocial treatments clearly
  asserted
• Strategies for medication dosing also described
• Published in JAACAP, July 2000 (Pliszka,
  Greenhill et al.)

114
Texas Medication Algorithm Project ADHD Without
Comorbidity
115
Texas Medication Algorithm Project ADHD Plus
Depression/Anxiety
116
Texas Medication Algorithm Project ADHD with
Comorbid Tic Disorder
117
Texas Medication Algorithm Project ADHD with
Comorbid Intermittent Explosive Disorder
118
Strategies for Treating ADHD with Comorbid
Bipolar Disorder

• Effective mood stabilization may be necessary
  before patients will respond to stimulants
• Stimulants will be used in combination with mood
  stabilizers/antipsychotics
• Many patients have histories of failed stimulant
  trials, or use of high doses of stimulant before
  bipolar disorder identified

119
Summary

• ADHD may have multiple causes, but is clearly a
  neurobiologically based condition
• ADHD patients are vulnerable to a variety of
  comorbid emotional and behavioral disorders
• Pharmacotherapy with stimulant medication is the
  single most effective treatment for ADHD, but
  clear benefits have been described for multimodal
  treatment interventions
• The Texas Medication Algorithm Project provides
  useful guidelines for treating ADHD accompanied
  by commonly seen comorbid conditions